Total callosotomy ameliorates epileptic activity and improves cognitive function in a patient with Miller-Dieker syndrome.

Miller-Dieker syndrome (MDS) is characterized by facial abnormalities and lissencephaly and is caused by a microdeletion in the region containing the LIS1 gene at chromosome 17p13.3. We report a case in which postnatal neuroimaging revealed severe lissencephaly. A 9-month-old boy presented with infantile spasms syndrome. Because of the refractory course of seizures and continued poor vitality, total corpus callosotomy was performed at 28 months of age. Intraoperative electroencephalogram (EEG) showed that the bilateral synchronous epileptiform discharges disappeared immediately after the disconnection. Postoperatively, the epileptic spasms (ES) in clusters disappeared, and single ES followed by focal seizures became the main symptom. The patient smiled more and became more responsive to stimuli. Postoperative scalp interictal EEG showed desynchronized multifocal spike and wave discharges with a marked decrease in the bilateral synchronous spike and wave discharges. Our findings suggest that the corpus callosum is involved in the mechanism ES in clusters in MDS-associated lissencephaly, and total callosotomy could be a therapeutic option.

Oxygen-Glucose Deprivation Increases NR4A1 Expression and Promotes Its Extranuclear Translocation in Mouse Astrocytes.

Hypoxic-ischemic brain injury induces metabolic dysfunction that ultimately leads to neuronal cell death. Astrocytes, a type of glial cell, play a key role in brain metabolism; however, their response to hypoxic-ischemic brain injury is not fully understood. Microglia were removed from murine primary mixed glial cultures to enrich astrocytes. Next, we explored genes whose expression is altered following oxygen-glucose deprivation using a microarray. Microarray analysis revealed that the expression of Nr4a1 and Nr4a3 is markedly increased in astrocyte-enriched cultures after 15 h of oxygen-glucose deprivation. The expression of both Nr4a1 and Nr4a3 was regulated by HIF-1α. At the protein level, NR4A1 was translocated from the nucleus to the cytoplasm following oxygen-glucose deprivation and co-localized with mitochondria in apoptotic cells; however, its localization was restored to the nucleus after reoxygenation. Oxygen-glucose deprivation causes an increase in NR4A1 mRNA in astrocytes as well as its nuclear to cytoplasmic transfer. Furthermore, reoxygenation enhances NR4A1 transcription and promotes its nuclear translocation.

Late relapse of anti-N-methyl-d-aspartate receptor encephalitis with amusia and transiently reduced uptake in 123I-iomazenil single-photon emission computed tomography.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis has a high relapse rate at approximately 10-20%. Most relapses occur within 2 years from onset, and 5 years after onset is rare. We report a case of anti-NMDAR encephalitis relapse with amusia 10 years after the initial encephalitis and discuss the usefulness of 123I-iomazenil single-photon emission computerized tomography (IMZ-SPECT) for its diagnosis. CASE: A 13-year-old left-handed girl presented with a depressed level of consciousness and focal to bilateral tonic-clonic seizures. Cerebrospinal fluid (CSF) analysis showed a mildly increased white blood cell count, elevated neopterin levels, and positive oligoclonal bands. Brain MRI was normal. IMZ-SPECT revealed reduced uptake in the right frontoparietal region. She received intravenous pulse methylprednisolone (IVMP) and high-dose intravenous immunoglobulin for autoimmune encephalitis; her symptoms resolved without neurological deficits. At 23 years old, she had mild right-sided numbness, dysarthria, amusia, and tonic-clonic seizures. Although the CSF analysis and brain MRI were normal, IMZ-SPECT revealed reduced uptake, indicating a relapse of encephalitis. IVMP administration resolved the symptoms. After discharge, the initial and relapse CSF analysis revealed anti-NMDAR antibodies. CONCLUSION: An anti-NMDAR encephalitis relapse 10 years after onset has never been reported. IMZ-SPECT may help in the diagnosis of anti-NMDAR encephalitis.

A case of focal cortical dysplasia type IIa with pathologically suspected bilateral Rasmussen syndrome.

BACKGROUND: Rasmussen syndrome (RS) is a rare neurological disorder characterized by unilateral chronic inflammation, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. There has been no detailed pathological evaluation or finding, including focal cortical dysplasia, for bilateral RS. CASE REPORT: A 13-year-old boy presented with status epilepticus with focal to bilateral tonic clonic seizure starting from the left upper limb. At the age of 15, epilepsia partialis continua of the right face and upper extremities appeared, and MRI showed hemispheric abnormal signal intensities with left frontal lobe predominance. Three months later, MRI showed extensive abnormal signal intensities in the right occipitoparietal and left temporal lobes. Tacrolimus was useful in preventing recurrence. Because the seizures were intractable, a corpus callosotomy was performed at 16 years along with a concurrent brain biopsy from the bilateral lateral frontal cortices. We detected dysmorphic neurons in addition to inflammatory changes suspicious for RS, leading to a diagnosis of focal cortical dysplasia (FCD) type Ⅱa and suspected bilateral RS. Total callosotomy and vagus nerve stimulation were not sufficiently effective. CONCLUSIONS: In bilateral RS, FCD may be present in both cerebral hemispheres. In the current case, an autoimmune response to dysmorphic neurons may have contributed to the pathogenesis of intense inflammation.

Evaluation of the Diagnostic Criteria for Anti-NMDA Receptor Encephalitis in Japanese Children.

OBJECTIVE: To evaluate the validity of the 2016 clinical diagnostic criteria proposed for probable anti-NMDA receptor (NMDAR) encephalitis in children, we tested the criteria in a Japanese pediatric cohort. METHODS: We retrospectively reviewed clinical information of patients with neurologic symptoms whose CSF was analyzed for NMDAR antibodies (NMDAR-Abs) in our laboratory from January 1, 2015, to March 31, 2019. RESULTS: Overall, 137 cases were included. Of the 41 cases diagnosed as probable anti-NMDAR encephalitis (criteria-positive) according to the 2016 criteria, 13 were positive and 28 were negative for anti-NMDAR-Abs. Of the 96 criteria-negative cases, 3 were positive and 93 were negative for anti-NMDAR-Abs. The sensitivity of the criteria was 81.2%, specificity was 76.9%, positive predictive value (PPV) was 31.7%, and negative predictive value was 96.9%. Compared with the true-positive group, the false-positive group contained more male than female patients (male:female, 4:9 in the true-positive vs 19:9 in the false-positive group, p = 0.0425). The majority of the cases with false-positive diagnoses were associated with neurologic autoimmunity. CONCLUSION: The clinical diagnostic criteria are reliable for deciding to start immunomodulatory therapy in the criteria-positive cases. Low PPV may be caused by a lower prevalence of NMDAR encephalitis or lower level of suspicion for encephalitis in the pediatric population. Physicians should therefore continue differential diagnosis, focusing especially on other forms of encephalitis. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the proposed diagnostic criteria for anti-NMDAR encephalitis in children has a sensitivity of 81.2% and a specificity of 76.9%.

De novo ATP1A3 variants cause polymicrogyria.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome.

OBJECTIVE: Increasing reports suggest a role for immunological mechanisms in febrile infection-related epilepsy syndrome (FIRES). The objective of this study was to elucidate the efficacy and safety of intrathecal dexamethasone therapy (IT-DEX). METHODS: We assessed six pediatric patients with FIRES who were administered add-on IT-DEX in the acute (n = 5) and chronic (n = 1) phases. We evaluated clinical courses and prognosis. We measured cytokines/chemokines in cerebrospinal fluid (CSF) from FIRES patients at several points, including pre- and post-IT-DEX, and compared them with control patients with chronic epilepsy (n = 12, for cytokines/chemokines) or with noninflammatory neurological disease (NIND, n = 13, for neopterin). RESULTS: Anesthesia was weaned after a median of 5.5 days from IT-DEX initiation (n = 6). There was a positive correlation between the duration from the disease onset to the introduction of IT-DEX and the length of ICU stay and the duration of mechanical ventilation. No patient experienced severe adverse events. Seizure spreading and background activities on electroencephalography were improved after IT-DEX in all patients. The levels of CXCL10, CXCL9, IFN-γ, and neopterin at pre-IT-DEX were significantly elevated compared to levels in epilepsy controls, and CXCL10 and neopterin were significantly decreased post-IT-DEX, but were still higher compared to patients with chronic epilepsy. IL-6, IL-8, and IL-1ß were significantly elevated before IT-DEX compared to epilepsy controls, though there was no significant decrease post-treatment. INTERPRETATION: IT-DEX represents a therapeutic option for patients with FIRES that could shorten the duration of the critical stage of the disease. The effect of IT-DEX on FIRES might include cytokine-independent mechanisms.

Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis.

PURPOSE: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy. METHODS: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP. RESULTS: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01). CONCLUSION: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.

Neurocritical care and target immunotherapy for febrile infection-related epilepsy syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is an intractable neurological disease characterized by an unexplained refractory status epilepticus triggered by febrile infection. A Consensus definition of FIRES was proposed in 2018, and its clinical features and prognosis are gradually being clarified. However, the development of effective treatments has been hindered as the etiology of this rare disease is as yet unelucidated. The basic approach to the management of FIRES, like other forms of epilepsy, is based on the control of seizures, however seizures are extremely intractable and require intravenous administration of large doses of anticonvulsants, mainly barbiturates. This treatment strategy produces various complications including respiratory depression and drug hypersensitivity syndrome, which make it more difficult to control seizures. Consequently, it is crucial to predict these events and to formulate a planned treatment strategy. As well, it is important to grow out of conventional treatment strategies that rely on only anticonvulsants, and alternative therapies are gradually being developed. One such example is the adoption of a ketogenic diet which may lead to reduced convulsions as well as improve intellectual prognosis. Further, overproduction of inflammatory cytokines in the central nervous system has been shown to be strongly related to the pathology of FIRES which has led to attempts at immunomodulation therapy including anti-cytokine therapy.

Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations.

Several recent studies have reported potassium sodium-activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial. We herein report the cases of four patients with KCNT1 mutations treated with quinidine. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 µg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 µg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 µg/ml. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.

Chronic dysfunction of blood-brain barrier in patients with post-encephalitic/encephalopathic epilepsy.

PURPOSE: This study aimed to elucidate the characteristics and effects of chronic blood-brain barrier (BBB) dysfunction in patients with post-encephalitic/encephalopathic epilepsy (PEE), using brain images and the cerebral spinal fluid (CSF)/serum albumin ratio (albumin quotient, QAlb) as a marker of BBB function. METHODS: We examined the albumin levels in CSF and serum samples from 312 patients with refractory epilepsy in our center between 2004 and 2015. Sixty samples from patients with PEE and 97 samples from age- and sex-matched disease controls (DC) were evaluated. We classified PEE patients into a widespread lesion group and a focal lesion group by severity on brain magnetic resonance images in the chronic phase after acute encephalitis/encephalopathy. RESULTS: Median QAlb was higher in PEE than in DC [median (range) ×103: PEE 3.6 (1.0-10.3) versus DC 2.7 (1.0-6.7), p = 0.007]. In a linear regression analysis of the relationship between QAlb and patient's age at CSF examination or duration of epilepsy, the slope of the regression line was greater in PEE than in DC. Furthermore, in patients under ten years of age, linear regression analysis of QAlb versus seizure frequency showed a weak but positive correlation. Among PEE patients, seizure frequency was higher in the widespread lesion group than in the focal lesion group [300 (4-3000) versus 30 (1-1500) seizures/month, p < 0.001]. CONCLUSION: Our study suggests that patients with PEE have more severe BBB dysfunction, and that the BBB dysfunction is associated with refractory epilepsy.

Influence of Inflammation on the Pharmacokinetics of Perampanel.

BACKGROUND: It is well-known that the pharmacokinetics of various drugs are influenced by inflammation. This study evaluated the relationship between C-reactive protein (CRP; an inflammation marker) and the pharmacokinetics of perampanel. METHODS: Among 111 patients who underwent measurement of both CRP and perampanel, 23 patients had a serum CRP level exceeding 1.5 mg/dL (CRP-positive). We compared the concentration/dose ratio (CD ratio) of perampanel in these 23 patients between the times when they were CRP-positive and CRP-negative. To evaluate the effect of CRP on the CD ratio, multiple regression analysis was performed with the following covariates: CRP-positive status, body weight, and use of phenytoin, carbamazepine, or phenobarbital, and combinations of these drugs. RESULTS: In 10 patients using enzyme-inducing antiepileptic drugs (AEDs), the mean CD ratio increased by 53.5% [from 1389 to 2132 (ng/mL)/(mg/kg)] when they were CRP-positive. In 13 patients without enzyme-inducing AEDs, the mean CD ratio increased by 100.8% [from 3826 ng/mL to 7683 (ng/mL)/(mg/kg)] when they were CRP-positive. By multiple regression analysis, the CRP level was a significant independent determinant of the CD ratio of perampanel. Despite a marked increase of the CD ratio, no adverse events were reported. CONCLUSIONS: Irrespective of concomitant administration of enzyme-inducing AEDs, the serum perampanel concentration showed a marked increase in patients with inflammation. However, this increase was not associated with central nervous system toxicity. Although it is unknown whether the concentration of free and/or bound perampanel was increased, it seems likely that dose reduction is unnecessary for elevation of the serum perampanel level in patients with inflammation.

A child with acute transverse myelitis requiring permanent pacemaker implantation.

We diagnosed a 3-year-old girl with acute transverse myelitis (ATM). She presented with weakness of the limbs and developed urination difficulty and respiratory disturbance. Magnetic resonance imaging revealed a symmetric area of high signal intensity on T2-weighted images involving the lower end of the medulla oblongata to the level of the fourth thoracic vertebra. Anti-aquaporin-4 antibody was negative. She was treated with intravenous methylprednisolone pulse therapy, immunoglobulin therapy, and plasmapheresis; however, her clinical symptoms did not change. At 10 and 20days after symptom onset, cardiac arrest occurred on postural change, requiring cardiopulmonary resuscitation. A permanent pacemaker was implanted 23days after onset. In the presence of sympathetic nerve hypofunction, relative hyperactivity of the parasympathetic nerves may have led to severe bradycardia and cardiac arrest in the presence of an inducer, such as a postural change. This is the first reported case of pacemaker implantation for management of ATM.

[A case of West syndrome with a deletion at chromosome 2q24.3-q31.3].

A male infant suffered from partial seizures at four months of age, and developed West syndrome at eight months of age. ACTH therapy was effective for the West syndrome. However, partial seizures recurred at 14 months of age, which could not be sufficiently controlled with an anti-epileptic drug. A characteristic facial appearance, great toe abnormalities, and developmental retardation were noted. An interstitial deletion of 2q was detected by chromosomal G-banding and array comparative genomic hybridization (CGH) confirmed the deletion as arr 2q24.3q31.3 (166,303,447-180,982.972) ×1 (build19). He presented with clinical findings similar to those of the recently defined 2q31.1 deletion syndrome. The deletion extended to the SCN1A gene, a gene responsible for Dravet syndrome, mapped to the 2q24.3 region. No deletion was noted in the adjacent SCN2A gene. Thus, for interstitial deletions, detailed breakpoints should be identified by array CGH. The frequency of epilepsy varies with deletion ranges in the 2q24-q31 region, suggesting that deletions in the SCN1A gene deletion, as well as in the 2q31.1 region, are involved in the development of West syndrome.

A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy.

INTRODUCTION: Mutations of SLC35A2 that encodes Golgi-localized Uridine diphosphate (UDP)-galactose transporter at Xp11.23 lead to congenital disorders of glycosylation (CDG). Although patients with CDG generally have diverse systemic symptoms, patients with a SLC35A2 mutation manifest predominantly disorders of the central nervous system (CNS). CASE REPORT: A female infant aged 12months was referred to our center because of intractable seizures. The patient was born with birth weight of 3228g after 40weeks of unremarkable gestation. At the age of 2months, she had partial seizures evolving to epileptic spasms. Her electroencephalogram showed hypsarrhythmia. Her seizures were refractory to antiepileptic drugs. At referral to our center at 12months, she had developmental delay (no head control), widely spaced inverted nipples, external strabismus, and bilateral heterochromia of irises. Blood examinations were normal. Brain magnetic resonance imaging findings included cerebral and cerebellar atrophy, thinning of the corpus callosum, and arachnoid pouch. Whole-exome sequencing detected a de novo frameshift mutation c.950delG (p.Gly317Alafs*32) at exon 4 in SLC35A2. Seizures subsided after the second adrenocorticotropic hormones (ACTH) therapy at 18months. At the age of 36months, although she had intellectual disability with no meaningful words, she was seizure-free and was able to sit without support and showed smiling face a lot. CONCLUSION: This report reviewed the clinical features of patients with a SLC35A2 mutation. ACTH therapy may be effective for refractory epilepsy in these patients.

A pediatric patient of hemorrhagic acute transverse myelitis.

An 11-year-old boy presented with progressive leg hypesthesia but no history of trauma. Dysuria and constipation appeared subsequent to gait difficulty. He was admitted 8days after onset. Spinal magnetic resonance imaging (MRI) revealed longitudinal hyperintensity with cord swelling and hypointensity on T2-weighted images, suggesting severe inflammation and microbleeding change, respectively. Gadolinium contrast-enhanced MRI demonstrated mild enhancement in the lesions. Platelet count and coagulation findings were normal, and cerebrospinal fluid analysis showed no pleocytosis. He was diagnosed with idiopathic acute transverse myelitis (ATM), and intravenous methylprednisolone pulse therapy and plasmapheresis were initiated. On day 14, motor dysfunction aggravated suddenly, accompanied by expanding hemorrhagic lesions. Thereafter, administration of intravenous immunoglobulin, repeated intravenous methylprednisolone pulse therapy and prednisolone for one month resulted in complete recovery four months later. Both anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative. We presented the first pediatric case showing hemorrhagic spinal lesions in the clinical course of ATM. This severe complication should be recognized in the management of ATM.

A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression.

BACKGROUND: Clinical phenotypic expression of SSADH deficiency is highly heterogeneous, and some infants may develop refractory secondary generalized seizures. PATIENT: A 9-month-old boy manifested partial seizures, developing severe status epilepticus, and conventional antiepileptic drugs were ineffective. Use of ketamine contributed to the control of status epilepticus, achieving a reduction in frequency of partial seizures, and improving EEG findings without apparent complications. Diffusion-weighted images showed hyperintensities in the bilateral basal ganglia and fornix, and multiple T2 hyperintensity lesions were detected. (123)I-iomazenil (IMZ) SPECT revealed a decrease in binding of (123)I-iomazenil predominantly in the left temporal region by the 18th day of hospitalization. However, repeated IMZ-SPECT on the 46th day of hospitalization demonstrated almost no accumulation across a broad region, sparing the left temporal region. The patient showed rapid regression, refractory myoclonus, and severe progressive brain atrophy. CONCLUSION: IMZ-SPECT findings demonstrated reduced benzodiazepine receptor binding and its dynamic changes in an SSADH-deficient patient. Considering the down regulation of the GABAA receptor, ketamine should be included in pharmacotherapeutic strategies for treatment of refractory status epilepticus in SSADH-deficient patients.

Autoimmune autonomic ganglionopathy in a pediatric patient presenting with acute encephalitis.

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to systemic autonomic failure. Autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR) are detected in 50% of AAG patients. We report the first pediatric case of AAG presenting with acute encephalitis. The patient was a 13-year-old boy who presented with orthostatic hypotension, followed by rapidly progressing disturbance of consciousness. Cerebrospinal fluid analysis revealed significant pleocytosis and increased neopterin concentration. Head MRI showed hyperintensities in bilateral caudate nuclei, putamen, hippocampus, and insula cortex. Severe autonomic dysfunctions such as severe orthostatic hypotension, bradycardia, dysuria, prolonged constipation and vomiting appeared. These symptoms were successfully controlled by repeated immunomodulating therapy with intravenous methylprednisolone pulse therapy and intravenous immunoglobulin. Autoantibodies to the α3 subunit of gAChR were detected at neurological onset, but were undetectable five months later. This observation indicates that AAG should be suspected in patients manifesting acute encephalitis characterized by preceding and prolonged autonomic symptoms, and immunomodulating therapy from an early stage can be effective.