Search

Tumefactive demyelinating lesions (TDL), defined as inflammatory demyelinating lesions, may develop either during treatment for multiple sclerosis and related disorders or as the first demyelinating episode without any past medical history suggesting demyelination. If the latter, it would be so delicate to diagnose as demyelination. Especially in such situations, biopsy is often necessary in addition to neuroimaging for distinction TDL with tumorous or infectious diseases. In this article, we will review about concept, epidemiology, diagnosis, and treatment of TDL.

Pediatric multiple sclerosis accompanied by a tumefactive demyelinating lesion (TDL) is extremely rare. Because it is very difficult to distinguish TDLs from neoplasms, invasive brain biopsies are required for a definitive diagnosis. MR spectroscopy (MRS) without brain biopsy was recently shown diagnostic in some patients with TDLs, based on the elevation of glutamate/glutamine peaks. This report describes the clinical course of a 9-year-old girl with multiple sclerosis following a TDL and discusses the usefulness of MRS and brain biopsies to diagnose TDLs.

Abnormalities in both the nervous and immune systems are thought to be relevant to the pathogenesis of multiple sclerosis (MS). Several functional molecules closely related to axonal regeneration play an important role in not only the nervous system, but also the immune system. Many recent studies revealed that these molecules are associated with the neurological and immunological aspects of the pathogenesis of MS. Therefore, we focused on these molecules as promising biomarkers for MS. Nogo protein and its receptor (Nogo receptor-1; NgR1) are well known representative molecules that prevent axonal regeneration, and we identified lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of NgR1. We found that LOTUS expression was decreased in the spinal cord in an experimental autoimmune encephalomyelitis mouse model and that variations in LOTUS concentration in the cerebrospinal fluid correlated well with disease activity in MS patients. On the other hand, previous studies have shown that repulsive guidance molecule-a and semaphorins, known to be involved in axonal guidance and regeneration, play a role in MS pathogenesis. We review the association of these molecules with the neurological and immunological aspects of MS pathogenesis, and we show that they are promising, clinically-relevant biomarkers for MS.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune and inflammatory diseases of the central nervous system. MS is considered an 'oligodendrocytopathy' with undefined autoantibodies, whereas NMO is considered an 'astrocytopathy' with aquaporin-4 antibodies. Both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, recent interest in gray matter (GM) pathology is emerging. Pathological evaluations reveal that substantial cortical demyelination is prominent at all stages or courses of MS. In addition, the neurodegeneration in MS is present not only in GM demyelination but also in normal-appearing GM. NMO involves cortical neurodegeneration and unique dynamics of astrocytes; however, no cortical demyelination is seen. Thus, MS and NMO are distinct diseases with unique pathological features in the brain WM and GM. Although the cause of GM and WM lesions in MS and NMO has not been fully determined, improved knowledge about the pathomechanisms in affected brains is desired. This would result in a more targeted pharmacotherapeutic approach to these diseases.

Multiple sclerosis (MS) is an autoimmune disease targeting oligodendrocyte in the central nervous system and involves heterogeneous pathology that yields considerable nonresponders to the first line therapy interferon (IFN)-β. However, determinants for this clinical efficacy have not been elucidated. Interestingly, an MS-like autoimmune disease neuromyelitis optica (NMO) is exclusively resistant to this therapy and mediated by IL-6-dependnet PBs via producing a disease-specific autoantibody against aquaporin 4 (AQP4) on astrocyte. Therefore, we assumed that IFN-β-nonresponsive patients with MS may have the similar B-cell abnormality and found an expansion of circulating PBs in these nonresponders. In addition, these PBs exhibited an IL-6-dependent survival in vitro like those in NMO. Clinical features of such "PB-high" patients were consistent with antoantibody-mediated pathology. Thus, we are administering anti-IL-6 receptor blocking antibody tocilizumab to these intractable patients with MS to achieve precision medicine for MS.

Pathological destruction of the blood-brain barrier(BBB) has been considered to be the initial key step of disease process in multiple sclerosis (MS) and neuromyelitis optica (NMO). The pathological findings using autopsy brain section from patients with secondary progressive (SP) MS or relapsing MS demonstrated a leaky BBB in active lesions and our recent data also showed that the sera from patients with relapsing MS or SPMS can induce the BBB breakdown. Recently, the disease-specific autoantibody "anti-aquaporin 4(AQP4) antibodies" was detected in the sera of NMO patients. Because the circulating anti-AQP4 antibodies need to pass through BBB in order to reach the astrocytic endfeets, where AQP4 localized, our recent studies demonstrated the detailed molecular mechanism of the BBB disruption in NMO.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating diseases of the central nervous system (CNS). The pathological hallmark of MS is sharply demarcated demyelinating plaques with the relative preservation of axons, suggesting autoimmune responses target CNS myelin. In contrast, NMO shows selective and severe attacks of both axons and myelin of the optic nerves and spinal cord, resulting in necrotic cavitation. Neuropathological studies have demonstrated extensive loss of aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and activated complements are deposited. We recently demonstrated the extensive loss of connexins(Cxs) in active lesions of Baló's disease, MS and NMO. Early disruption of Cx gap junction among glial cells may be a common denominator in heterogeneous human demyelinating conditions. This review aims to discuss the molecular pathology of MS and NMO that have attracted the most attention in the recent years.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system(CNS). MS is assumed to be caused by a complex interplay between genes and environments. Autoimmune mechanisms targeting CNS myelin has long been proposed, yet it has not been proved. Th17 cells producing interleukin-17 and Th1 cells producing interferon-gamma are postulated to play major roles in initiating inflammation while regulatory T cell functions are dampened. The forth nationwide survey of MS in Japan revealed that MS prevalence showed four-folds increase over 30 years and the increase was especially prominent in female. Thus, westernized life style and improved sanitation are suspected to increase MS susceptibility. Genome-wide association studies in Western MS patients disclosed more than 100 disease-susceptibility genes, most of which are immune-related genes. It therefore supports immune-mediated mechanisms to be operative. Detailed magnetic resonance imaging studies revealed an early atrophy of the cerebral gray matter where T cell infiltration is pathologically scarce. Therefore, neurodegenerative process also takes place in the early course beside neuroinflammation.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune and inflammatory diseases of the central nervous system (CNS), and conventional magnetic resonance imaging (MRI) is a currently-established tool in the diagnosis of these two diseases. More recently, the utility of both conventional MRI and advanced MR techniques including structural, metabolic and functional MRI have provided new surrogate markers of clinical activity and prognosis. This review focuses on the current knowledge of the details of radiological examination in two distinct diseases, MS and NMO, and clarifies that each has unique characteristic features of radiological and pathological modalities in the CNS. However, advanced MR techniques still need to be fully evaluated and validated by pathological studies.

Cognitive impairment may occur in up to 70% of all patients with multiple sclerosis (MS). Although MS can affect various sites within the central nervous system, a specific pattern of cognitive deficits tends to be seen, especially in the early stages of the disease. These deficits include problems with attention, information processing speed, and working memory. This constellation of deficits can occur with any disease course, and a minimal correlation has been found between physical disability assessed by EDSS and cognitive impairment. Many studies have shown that cognitive impairment is correlated with brain lesion volume, as well as brain atrophy. There are promising neuroimaging indicators that may be useful for identifying patients at risk for cognitive impairment, such as diffusion tensor imaging, the magnetization transfer ratio, and N-acetyl aspartate levels. Cognitive dysfunction is associated with adverse effects on quality of life, employment status, and social activities. Today, there are three avenues for treatment: disease modifying therapies, symptomatic treatments, and cognitive rehabilitation. Unfortunately, data linking therapeutic interventions are limited. A better understanding of cognitive function and its correlation with disease mechanisms will assist in providing a new comprehensive treatment strategy that begins immediately with the diagnosis of MS.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), in which inflammation develops upon leukocyte invasion into the CNS via the blood-brain barrier. α4-Integrin is an important cell adhesion molecule involved in the penetration process. Natalizumab is an α4-integrin-targeting monoclonal antibody that was recently approved for use as a disease-modifying therapy for MS in Japan. In this article, the mechanism of action, efficacy, and side effects of natalizumab will be reviewed.

It is of key importance to be able to evaluate the temporal changes seen in multiple sclerosis (MS) lesions in terms of location, shape, and area for estimating MS progression. The purpose of our study was to develop an automated method for detecting potential MS regions based on three types of brain magnetic resonance (MR) images: T1- and T2-weighted images, and fluid attenuated inversion-recovery (FLAIR) images. The brain regions were segmented based on a tri-linear interpolation technique and k-mean clustering technique. True positive regions and false positive regions were classified from three types of MR images using a support vector machine (SVM). We applied our proposed method to 60 slices of 20 MS cases. As a result, the sensitivity for detection of MS regions was 81.8%, with 14.1% false positives per true positive. This method should prove useful for the diagnosis of multiple sclerosis.

The precise mechanisms of cortical damage in multiple sclerosis (MS) remain unknown. Microglia, the resident immune cells in the central nervous system (CNS), are involved in the chronic neuroinflammation in MS cortical lesions. Microglia produce various inflammatory cytokines such as IFN-γ and IL-β, reactive oxygen species, and glutamate. IL-β secretion is induced by NLRP3. ROS is induced by GM-CSF-producing Th17 cells. Glutamate is released via gap junctions. These molecules exert neurotoxicity. Meanwhile, damaged neurons produce fractalkine and FGF-2, which suppress microglial activation and enhance microglial neuroprotection through anti-inflammatory and anti-oxidant effect. Fractalkine accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. FGF-2 induces microglial migration through the FGFR3-Wnt-ERK signaling pathway. These molecules suppress microglial neuroinflammation, and enhance neuroprotection, which may give us clues for future therapeutic strategy cortical damage in MS.

Around a half of multiple sclerosis (MS) patients suffer from cognitive impairment such as attention deficit. A similar impairment is already observable in one third of patients with clinical isolated syndrome, suggesting that the symptom cannot be solely explained by the accumulation of demyelinated lesions. Recently, several studies indicated that demyelination and atrophy in specific regions of the brain are related to the cognitive impairment, although those patients with brain and cognitive reserves are resistant to the development of such symptom. Aging, male sex and smoking increases whereas certain disease-modifying therapy decreases the risk of cognitive impairment in MS. Together, the development of cognitive impairment in MS appears to be determined by the balance between specific aggravating and protective factors.

Multiple sclerosis (MS) has long been considered to be the autoimmune disease that primarily affects oligodendrocyte and myelin in the white matter (WM) of the CNS. However, renewed interest in the gray matter (GM) pathology including cortical and deep GM of MS is emerging. Radiological and pathological assessments demonstrate that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present in even normal-appearing GM in MS. Patients with MS have cognitive impairment as represented by the latent start of impairment from the very early stage of the disease course, and not only WM lesions but also GM lesions might be good predictors for cognitive impairment in MS. Although the cause of the GM lesions in MS has not been fully determined, an increase in knowledge of the structure of GM lesions in MS brains will result in more targeted therapeutic approaches to the disease.

Recently, neural oscillations, especially gamma oscillation (>30 Hz) has been paid attention in the Systems Neuroscience. In monkey, neural oscillations are involved in either intrahemispheric or interhemispheric integrative brain function. Magnetoencephalography (MEG) provides information on human brain functions with the excellent temporal (ms) and spatial (mm) resolution. This technique allows us to identify when, where and how bran works. Here, I present the recent findings in our laboratory on the disruption of the neural network in human.

The prevalence of multiple sclerosis (MS) in Japan has been increasing in recent years, and general physicians should be alert for early and correct diagnosis of this disorder. For this purpose, the 2010 revisions to the McDonald criteria are helpful, as they employed simplified parameters for magnetic resonance imaging (MRI) findings to confirm dissemination in space (DIS) as well as dissemination in time (DIT). However, physicians must also carefully consider medical history, combinations of neurological symptoms and signs, and findings obtained from cerebrospinal fluid samples and/or electrophysiological tests for individual diagnoses. Thus, establishment of more specific and sensitive criteria in the near future will help to recruit very early MS patients for disease-modifying therapies, leading to better prognosis.

Diagnosis of multiple sclerosis (MS) is difficult when the lesion mimics glioma or cerebral enchephalitis. We report a case of pediatric MS initially suspected as brain stem glioma. An 11-year-old boy developed left foot joint pain followed by progressive symptoms such as left arm and leg weakness, dysarthria, paraplegia, and decreased level of consciousness. He subsequently developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Magnetic resonance imaging showed a mass measuring 2 cm in the medulla oblongata. Although this mass was initially suspected as a glioma, the patient's acutely progressive disease course was not consistent with this diagnosis. Open biopsy revealed inflammation and demyelination, but no malignant cells were detected. He was treated with steroid pulse therapy, which showed dramatic effects. Nine months later, he developed another episode characterized by several neurological symptoms, and the diagnosis of MS was clinically confirmed. Open brain stem biopsy is technically demanding, but this case demonstrates that appropriate neurosurgical evaluation can play an important role in diagnosis by ruling out glioma and confirming MS.

Demyelination shows different pathological changes spatially and temporarily, but conventional MRI cannot correctly demonstrate such pathological differences. Recently several advanced MRI techniques are introduced and especially magnetization transfer contrast, diffusion tensor imaging and MR spectroscopy are reported as the useful techniques to detect pathological and neurochemical differences on demyelinating diseases. By these newly-developed techniques, it may be possible to detect pathological and neurochemical changes on demyelinating diseases more correctly, leading to more appropriate therapy and correct prediction of patient's prognosis.

We present the case of a 31-year-old woman who developed N-methyl-d-aspartate (NMDA) receptor encephalitis during the course of relapsing and remitting multiple brain lesions. The patient developed a tingling sensation in the left upper and lower extremities, and was first admitted to our hospital at age 27. She was tentatively diagnosed with multiple sclerosis on the basis of multiple lesions with Gd-enhancement in the brainstem, and 2 separate clinical relapses by age 28. At age 31, she developed a headache and pyrexia, followed by confusion and abnormal behavior. Her symptoms acutely progressed to stupor, and subsequently, she developed oral dyskinesia and athetosis-like involuntary movement of the left arm. The stupor state continued over 2 months. However, she had completely recovered by 3 months after the onset of psychiatric symptoms. Her serum and CSF samples tested positive for anti-NMDA receptor antibodies, and she was diagnosed with NMDA receptor encephalitis. Her serum was negative for anti-AQP4 antibody, but showed weak positivity for antinuclear antibody. Between ages 32 and 34, she experienced 2 clinical relapses, including right-hand clumsiness, confusion, aphasia, and dysphagia. FLAIR images showed a high-intensity area in the brain stem, thalamus, and subcortical white matter. No tumors were found throughout the course. A clinical entity of NMDA receptor encephalitis can include various neurologic disorders, such as the development of recurrent demyelinating brain lesions. Further investigation is required to clarify the pathophysiological role of anti-NMDA receptor antibody in our patient.

Recently, we reported aquaporin-4 (AQP4) loss without perivascular deposition of complements or immunoglobulins in autopsied cases with multiple sclerosis (MS), neuromyelitis optica (NMO) and Baló's disease (BD). To investigate the relationship between astrocytopathy and demyelination, we examined the expression of connexins (Cx), which form gap junction channels between astrocytes and oligodendrocytes. We pathologically evaluated the expressions of astrocytic Cx43/Cx30 and oligodendroglial Cx47/Cx32 relative to those of other astrocytic and oligodendrocyte/myelin markers among the autopsied cases. In all BD cases, Cx43, Cx32 and Cx47 were extensively diminished. In the leading edge of Baló's lesions, Cx43 and AQP4 loss preceded Cx47 loss. Two cases with MS and six with NMO showed preferential Cx43 and AQP4 loss far beyond the demyelinated areas, while vasculocentric deposition of immunoglobulins or complements was observed in four of the six NMO cases. The other cases showed AQP4 and Cx43 preservation. Some NMO cases showed preferential myelin-associated glycoprotein (MAG) loss in AQP4- and Cx43-diminished active lesions. Our findings indicate that disruption of Cx gap junction and preferential MAG loss could occur in MS, BD and NMO, and could be a common denominator. Inhibition of Cx hemichannels is a possible therapeutic target for demyelinating disorders.

Treatment of patients with clinically isolated syndrome (CIS) with disease modifying drugs including interferon β delays conversion to clinically definite multiple sclerosis (MS). However, CIS patients do not necessarily develop MS even after 20 years. Brain MRI lesions were required for CIS patients to include in clinical trials such as CHAMPS study and BENEFIT study. CIS patients with brain MRI lesions compatible to MS were considered as high risk to convert to MS in western countries. Previously we reported that asymptomatic enhancing brain lesions (AEBLs) were found in 9/23 (39.1%) of MS patients who had suffered at least one relapse in the preceding year or two relapses in the preceding 2 years, and the number of AEBLs per scan was 0.37, suggesting low disease activity of Japanese MS patients. We examined brain MRI findings in Japanese CIS patients and compared with those of Japanese MS patients at the first presentation. We reviewed brain MRI of 23 CIS visited our clinic from December 2007 to October 2010 who fulfilled the criteria proposed by Kappos et al. (2006) and Dalton et al (2002). Thirty two clinically definite MS (CDMS) patients fulfilled the first McDonald criteria (two or more attacks and objective clinical evidence of two or more lesions) proposed by Polman et al. (2005). Patients with neuromyelitis optica (NMO) and patients with NMO spectrum proposed by Wingerchuk et al. (2006) and Wingerchuk et al. (2007), respectively, were excluded. Patients with anti-aquaporin4 antibodies or with contiguous spinal cord lesion extending over three vertebral segments on MRI were also excluded. We could not obtain MRI of 11 patients with CDMS because of very long disease course, and 2 CIS and 13 CDMS patients had not been examined with MRI. So we examined 21 CIS and 8 CDMS patients at the first presentation using Paty criteria and Barkhof criteria. Eleven CIS patients did not meet any of the Barkhof criteria. Seven and 3 CIS patients met one and two of Barkhof criteria, respectively. No CIS patients showed fulfilled more than 3 of Barkhof criteria. Seven of eight CDMS patients at the first presentation showed more than one of the Barkhof criteria, however, only one CDMS patient at the onset fulfilled more than 3 of the Barkhof criteria. Japanese CIS patients seemed to show less brain lesions than those in western countries.

Spontaneous remyelination occurs in many early multiple sclerosis (MS) patients, however its capacity decreases as the disease becomes chronic. Even in those chronic MS patients, an enough number of oligodendrocyte precursor cells (OPCs) are preserved within the demyelinated lesions, suggesting that the differentiation arrest of oligodendroglial cells underlies the remyelination failure in chronic MS. We have previously reported that TIP30, a factor inhibiting nucleocytoplasmic transport within the cell, is responsible for the differentiation arrest in MS lesions. Overexpression of TIP30 in the preserved OPCs in MS lesions results in the failure of nuclear translocation of transcription factors necessary for oligodendroglial differentiation. Therefore, anti-TIP30 therapy to regain the nuclear access within the OPCs is necessary for sufficient remyelination in chronic MS patients. Moreover, inflammatory conditions surrounding OPCs may be involved in the efficient remyelination in early MS lesions, alternative stimulatory factor may therefore be mandatory to induce OPC differentiation into oligodendrocytes within the chronic lesion. We have previously reported that targeting FcRγ protein on OPCs may stimulate their differentiation and consequently remyelination in the chronic lesions. A timely collaboration of these two approaches may be required for successful remyelination and neurological recovery in chronic MS patients.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. An antibody for aquaporin-4 (AQP4), which is a water channel located in astrocyte foot process, is specifically positive for NMO and antibody and complement dependent astrocytic damage is thought to be a main cause of NMO. Baló's disease is characterized by alternating rings of demyelination and preserved myelin. We pathologically compared the astrocytic changes among autopsied cases with these CNS demyelinating diseases. NMO, MS and Baló's disease shared with reduced AQP4 immunoreactivity independent of antibodies and complements. The pathological finding was accompanied with a reduced immunoreactivity of connexin 43 and perivascular lymphocytic cuffing predominantly composed by T cells. The loss of astrocytic proteins such as AQP4 and connexin 43 preceded the loss of myelin proteins in some lesions. These features suggest astrocyte damages resulting in the loss of connexin 43 cause demyelination through the impairment of interaction between astrocytes and oligodendrocytes and the pathomechanism involves a T cell reaction.

A 32-year-old woman, who had developed head tremor and paresthesia of the right upper limb for several months, was admitted to our hospital The diagnosis of multiple sclerosis was made because the serial MRI showed multiple lesions in both the cerebral white matter and the cervical cord. Oligoclonal IgG band was positive. Her symptoms were improved by intravenous methylprednisolone and an antiepileptic drug (MEPM 1 g/day and CZP 1 mg/day). The head tremor was the so-called "yes-yes" type which shakes back and forth. Although this type of tremor has been considered to be developed by the lesions in the cerebellum, our patient seemed to develop the tremor by cervical cord lesion. Further investigation is needed to confirm the association of the head tremor and the cervical lesions in MS.

We retrospectively analyzed and compared patterns of anti-aquaporin-4 (AQP4) immunoreactivity of autopsied brains of 2 patients with classical multiple sclerosis (MS) and 2 patients with neuromyelitis optica (NMO). Serological examination for NMO-IgG was not performed in all the cases. We confirmed that the expression of AQP4 is strongly inhibited in demyelinating lesions of NMO, accompanied by the loss of grial fibrillary acidic protein (GFAP) expression. The expression of AQP4 is preserved in MS lesions losing myelin basic protein (MBP) positivity. Therefore, AQP4 immunoreactivity may distinguish NMO from MS neuropathologically. NMO preferentially exhibited central lesions of the spinal cord with strongly necrotizing features and axonal injury. One NMO patient with oligoclonal band in the cerebrospinal fluid presented severe necrotizing lesions of the corpus callosum, cerebral white matter in addition to optic nerves and longitudinally extensive spinal cord lesions. Another patient with MS presented longitudinally extensive spinal cord lesions and a lesion in the medullary tegmentum in the floor of the fourth ventricle, which is reported to be one of the vulnerable lesions of NMO. We also reported a patient with NMO accompanied with Sjögren syndrome. These findings suggest that longitudinally extensive spinal cord lesions and medullary tegmentum lesion may be found in MS,and cerebral white matter lesion may be found in NMO. The distribution of lesions may overlap in MS and NMO although the immunoreactivity of AQP4 differs in these 2 conditions.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS). This disease is characterized by so-called "multiplicity in time and space in the CNS". Although the pathomechanisms of MS have been extensively studied for a long time, the etiology is still unknown. It has been pointed out that the prevalence rate of MS is very low, and that the optic spinal form of MS (OSMS), which mainly affects the optic nerves and spinal cord, is common in Japan. There has been a long controversy as to the differences between OSMS and neuromyelitis optica (NMO), and whether NMO or OSMS is a subtype of multiple sclerosis (MS) or a distinct disease. Recently, a highly disease specific autoantibody, NMO-IgG, was found in the sera of patients with NMO as well as OSMS. However, this antibody was not detected in the sera of MS patients. Therefore, we conclude that OSMS is the same as NMO, and speculate that NMO/OSMS may be a distinct disease from MS. Many investigations have revealed several differences clinically and pathologically between MS and NMO/OSMS. The following features such as female predominance, no brain lesions and longitudinally extended spinal cord lesions by MRI study and neuropathologically necrotic or cavitary lesions are commonly seen in NMO/OSMS. The most recent and important discovery that NMO-IgG reacts specifically with aquaporin 4 (AQP4), which is a water channel localized in astrocytes, opened new avenues for understanding the pathogenesis of NMO/OSMS. We immunocytochemically studied the expression of AQP4 in lesions of postmortem NMO/OSMS, and found that AQP4 was completely lost in the acute lesions. In addition, an astrocytic marker, GFAP, was also lost in the NMO/OSMS lesions. However, the myelin basic protein-stained fibers were relatively preserved. These immunocytochemical features are in contrast to those of MS. In MS, there was no loss of either AQP4 or GFAP expression in the lesions. Moreover, the values of GFAP were markedly increased in CSF from patients with NMO/OSMS in the acute phase but were never increased in patients with MS. These results strongly suggest that astrocytic impairment associated with AQP4 antibody may be mainly involved in NMO, and that the pathogenesis of NMO is distinct from MS, which is primarily a demyelinating disease.

Therapeutic options for patients with progressive multiple sclerosis are currently limited. This is in part due to lack of knowledge regarding the pathophysiology of the disease in this stage. This review summarizes recent findings, showing profound differences in the pathology between relapsing and progressive MS. Pathological hallmarks in progressive MS are slow expansion of pre-existing white matter lesions, massive cortical demyelination and extensive diffuse injury of the normal appearing white matter. As in relapsing MS also in progressive MS active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier. Different immunological mechanisms are involved in tissue destruction in progressive MS, but inflammation induced mitochondrial injury appears to be a dominant pathway. Future therapeutic interventions will have to target inflammation, which is compartmentalized in the central nervous system. In addition, however, neuroprotective therapies may be necessary.

A 26-year-old woman noticed gradually progressive, right lower leg weakness over a 1.5-month period. Neurological examination revealed right hemiparesis with slightly increased deep tendon reflexes, Babinski's sign on the right side, loss of position sense in the right leg, and slight loss of superficial sensation in the right toes. MR FLAIR images showed a high intensity area measuring 5 x 2 x 3 cm in the left frontal lobe, extending to the outer surface of the body of the corpus callosum and the adjacent right cingulate gyrus. Gadolinium enhancement was seen along the cortex and the outer surface of the body of the corpus callosum. CSF findings showed no pleocytosis, a protein content of 32 mg/dl, a sugar level of 85 mg/dl, and an IgG index of 0.46. The biopsy specimen obtained from the superior frontal gyrus showed perivascular cuffing of T-lymphocytes and some B-lymphocytes, as well as multiple small foci of demyelination. Starting on the second day of admission, the patient was treated with methylprednisolone pulse therapy (1,000 mg/day for 3 days); she was then switched to oral prednisolone (20 mg/day). Thereafter, the patient had two clinical relapses: one was due to a lesion in the dorsal part of the medulla oblongata associated with a disturbance of deep sensation in both hands, and the other was due to a lesion involving the right internal capsule, the globus pallidus, and the caudate nucleus associated with left facial nerve palsy. Visual evoked potentials suggested a demyelinating lesion in the right optic nerve. We suspected a diagnosis of multiple sclerosis based on the presence of more than two clinical episodes of neurological deficits with identifiable lesions on MRI. Multiple sclerosis should be considered in the differential diagnosis of lesions located in the outer part of the corpus callosum and transcallosal bilateral hemispheres on MRI, even though inner callosal lesions are common in multiple sclerosis.

We report a pediatric case of multiple sclerosis mimicking malignant brain tumor. A 11-year-old male presented with high fever, vomiting and partial convulsion of left lower extremity followed by left visual impairment. Magnetic resonance imaging (MRI) revealed a mass lesion in the right frontal lobe with significant peripheral edema. Incomplete ring-like enhancement by gadolinium administration was also noted. Open biopsy of the lesion was undertaken that provided pathological confirmation of demyelinating changes. Luxol fast blue stain and Bodian stain demonstrated extensive myelin loss and good preservation of axons. The patient was given intravenous high-dose methyl-prednisolone and sequential oral low-dose prednisone, which improved his neurological status progressively. The lesion was dramatically decreased in size and finally disappeared. Although many tumor-like demyelinating lesions were reported previously, pediatric cases of multiple sclerosis mimicking malignant brain tumor are extremely rare. Pathological examinations including Luxol fast blue stain and Bodian stain are essential for exact diagnosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). MS is classified into clinical subtypes, such as relapsing-remitting MS, primary and secondary progressive MS, benign MS and malignant MS. In Japan, the classification based on the lesion distribution is also commonly used. There are two subtypes in this classification, conventional MS, in which demyelinating plaques are disseminated within CNS, and optic spinal MS, or relapsing neuromyelitis optica, characterized by the selective involvement of the optic nerves and spinal cord. Clinical manifestations and MRI findings of the clinical subtypes and their immuno-pathology are reviewed with emphasis on the unique features of Japanese MS.

Proton magnetic resonance spectroscopy(1H-MRS), which provides biochemical information in not only visible lesions on conventional MR imaging but also normal appearing white matter(NAWM), has extended the genesis of multiple sclerosis(MS) in several important directions. First, serial 1H-MRS studies reveal dynamic regional biochemical alterations in plaques during the course of the illness. Second, axonal damage may occur at early stage. Third, neuronal loss can be substantial in the gray matter. Fourth, NAWM shows widespread biochemical involvement prior to detection on MRI. Fifth, severities of neuroaxonal involvement significantly correlate with neurological dysfunction. 1H-MRS will provide more detailed information than conventional MRI, and could be beneficial in monitoring effects of therapeutic interventions in MS.

Magnetic resonance imaging(MRI) is very useful as a method form confirming the lesion distribution of multiple sclerosis(MS). Although MS should be diagnosed primarily on clinical grounds, MRI aids the diagnosis by providing paraclinical evidence for the dissemination in both time and space. Recently, a new guideline for MS diagnosis was proposed by International Panel. This guideline set out to integrate MRI into the overall diagnostic scheme because of its unique sensitivity to pathological changes. In Japanese, however, the so-called optic-spinal form of MS, which is characterized by the selective involvement of the optic nerves and the spinal cord, is relatively common. Moreover, most of Japanese MS patients without oligoclonal bands show atypical brain lesions which do not fulfill the MRI criteria for brain abnormality.

A variety of cytokines are involved in the pathogenesis of multiple sclerosis(MS), either in induction phase and effector phase. In order to interact with immune cells, the cells in the brain have to express MHC antigens which they do not usually express. Cytokines such as IFN gamma, IL-3 and TNF alpha induce MHC antigen expression on neural cells. IFN gamma also induces costimulatory molecule for antigen presentation and also induce IL-12, a critical cytokine in T helper cell differentiation, in microglia. Although TNF alpha is a critical cytokines in effector phase, other cytokines and chemokines have also been shown to play roles on the development of inflammatory demyelination and gliosis. In this chapter, we will review the cytokine profile of MS lesions.

We have previously demonstrated that NK cells and CD1d-restricted NKT cells regulate clinical and pathological manifestations of experimental autoimmune encephalomyelitis(EAE), an animal model for multiple sclerosis(MS). It is important to address whether NK and NKT cells are also involved in the pathogenesis of human MS. Our laboratory has recently showed that NK cells as well as CD4+ NKT cells are biased for secreting type 2 cytokines in the remission phase of MS. However, CD4- CD8- NKT cells, that mainly secrete TNF-alpha and IFN-gamma, are reduced in number and attenuated in cytokine secretion. These results support our postulate that NK and NKT cells are involved in the regulation of MS.

An understanding of the natural history of multiple sclerosis(MS) in a patient is important to begin proper treatment at the correct time, especially when there is a high risk for poor prognosis. Factors that predict unfavorable prognosis are a primary or secondary progressive course, older age at disease onset, short interval between first and second attacks, initial cerebellar or pyramidal symptoms, a large number of functional systems involved at onset, moderate to severe disability within the first 2 years, and the presence of typical plaques or greater lesion volume shown by magnetic resonance imaging results during the first 5 years. However, there are no established laboratory tests able to predict long-term prognosis.

We report a rare case of a 31-year-old woman who was diagnosed as multiple sclerosis with homonymous hemianopia due to a demyelinative lesion in the lateral geniculate body. Paresthesia appeared in the distal parts of both legs from September, 2002. She complained of loss of visual field in both eyes 2 months later. Since a left asymmetric wedge-shaped homonymous hemianopia was detected by Octopus automatic perimetry, she was referred to our hospital on December 2, 2002. Neurological examination showed subjective paresthesia in the distal parts of both legs in addition to Lhermitte's sign. Brain MRI showed demyelinated lesions in the lateral geniculate body on the right and periventricular areas of the lateral ventricles. Spinal MRI revealed a demyelinated lesion in the upper cervical cord. She was diagnosed as multiple sclerosis and underwent a steroid pulse therapy. Homonymous hemianopia resolved a few days later.

A 13-year-old girl presented herself with right optic neuritis and pleocytosis in the cerebrospinal fluid (CSF) in May 2000. Although her vision gradually improved after steroid therapy, the right optic neuritis relapsed a month later, and MRIs of the brain showed multiple high-signal intensity areas in the white matter of the right frontal and parietal lobes on T2-weighted and FLAIR images. She developed nuchal pain, low-grade fever, and general malaise in January 2002. Mononuclear pleocytosis and an elevation of myelin basic protein level were noted in CSF (33/microliter, 17.7 ng/ml, respectively). In addition to the plaque-like lesions seen in June 2000, MRI at this time showed an increase in the number of plaques in the medulla, pons, bilateral cerebellar peduncles and cerebellum. We thus considered this case as MS presenting with no focal neurological deficits but meningitis and asymptomatic MRI lesions. The past history of relapsed optic neuritis is supportive and compatible with that diagnosis. One might assume that the case belongs to that of relapsed type acute disseminated encephalomyelitis (ADEM). However, the cardinal pictures of the case are those of relapsing optic neuritis and multiple asymptomatic plaques despite clinical remission. Some atypical features like meningitis may predominate in clinical presentations of child MS, since immune response in child may differ from that of adult.

We report a case of multiple sclerosis (MS) with pathological laughing for which lesions in pontine bases are considered to be responsible. A 30-year-old man was diagnosed as having MS based on left hemiparesis, and pathological laughing, and MRI findings showing a plaque in the right pontine base as well as several plaques in the bilateral periventricular deep white matter. After remission for 6 years, his pathological laughing exacerbated in association with development of right hemiparesis. A new lesion in the left pontine base was demonstrated by MRI studies in addition to a few supratentorial lesions. Steroid pulse therapy was effective for both pathological laughing and right hemiparesis. We speculate that the anatomical lesion responsible for the pathological laughing is located in the pontine base.