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Introduction: Brainstem symptoms can be the first manifestation of neuromyelitis optica (NMO) and related spectrum disorders (NMOSD). They can result from a cervical spinal cord lesion extending to the medullary region or as a brainstem-restricted lesion. These lesions commonly cause intractable nausea, vomiting and/or hiccups, however, oculomotor symptoms or ataxia are infrequent. Few studies have investigated the prevalence of brainstem symptoms in NMOSD. Materials and Methods: A retrospective study was conducted involving 206 NMO/NMOSD patients followed at the Hospital das Clínicas, University of São Paulo. Patients satisfied the Wingerchuk 2006 and 2007 diagnostic criteria for NMO/NMOSD. Brainstem lesions were evaluated using 1.5t MM. Aquaporin-4 (AQP4) antibody was tested using a cell-based assay. Results: From the total of patients, 46.6% (96/206) had NMO and 53.4% (110/206) had NMOSD. In the NMOSD group, 75 patients had longitudinally extensive transverse myelitis (LETM) and 35 had optic neuritis (ON). The anti-AQP4 was positive in 72.3% (149/206) of the cases. The clinical diagnosis of anti-AQP4+ cases were: NMO in 57.7% (86/149), LETM in 26.2% (39/149) and ON in 16.1% (24/149). Brainstem symptoms were the first clinical symptom of NMOSD in 17% (35/206) of the total and anti-AQP4 was positive in all these cases. Brainstem symptoms as a first attack without an extension of a cervical spinal cord lesion were seen in 13.6% (28/206) of cases and as an extension of LETM in 3.4% (7/206). Brainstem symptoms were present in at least one attack in 47.6% (98/206) of the patients, however, brainstem lesions on the MRI were found in only 40.8% (40/98) of these patients. No patients who presented exclusively with brainstem symptoms as the first attack without an extension of a cervical spinal cord lesion were properly diagnosed at the first attack. Discussion and Conclusion: Brainstem symptoms as the first manifestation of NMOSD may not be uncommon. NMOSD should be suspected in patients with intractable nausea, vomiting and/or hiccups, especially those with brainstem lesions on MRI. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are characterized by severe optic neuritis and myelitis attacks. The majority of these patients are positive to antibodies against aquaporin-4 (AQP4). NMOSD onset is concentrated during the fourth decade of life, although it can also affect pediatric and elderly patients. However, it is unknown if the clinical phenotype is influenced by age at onset. Materials and Methods: The sample included 72 consecutive patients followed at the Hospital das Clinicas, University of São Paulo (São Paulo, Brazil), all of whom fulfilled the Wingerchuk diagnosis criteria for NMOSD and were positive for anti-AQP4. Results: From the total number of patients, those with at least one episode of optic neuritis (ON) were younger than patients without ON (31 years vs. 47 years, p = 0.0008) and more frequently had brainstem symptoms (53.3% vs. 25.9%, p = 0.02). In the age subgroup analysis, optic nerve involvement was more frequent in patients aged between 3-20 years in comparison to patients aged 21-50 years and 51-70 years (92.3% vs. 62.2% vs. 35.7%, p = 0.0024), as well as brainstem involvement (61.5% vs. 46.7% vs. 14.3%, respectively, p = 0.0124). In contrast, patients with myelitis had a single attack in about a third of cases in comparison to 4.4% in patients with ON. In addition to multifocal presentation, young patients (3-20 years) had a higher number of attacks than older patients (6 attacks vs. 3 attacks, p = 0.0017). Discussion and Conclusion: ON and brainstem involvement are common in younger patients with a more aggressive course, while a third of cases with myelitis had a single attack. Younger patients may have some differences in their immune system and require a more aggressive treatment approach to avoid disability secondary to NMOSD attacks. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica (NMO) is a disease whose mechanism of humoral immunopatho-genesis was elucidated after the discovery of the anti-AQP4 antibody. Treatment in the acute phase aims to decrease functional disability. The current recommended approach in the acute phase is pulse therapy with methylprednisolone, followed by plasmapheresis in patients with a poor response. The benefit of the use of plasmapheresis in NMO has been demonstrated in some significant studies. The aim of this research was to evaluate the clinical response to plasmapheresis in all patients with outbreaks of NMO and NMO spectrum disorders, unresponsive to corticosteroids. Materials and Methods: Patients admitted to the Hospital das Clínicas of the University of São Paulo, Brazil during the period March to December 2013 were prospectively evaluated, post-procedure at time intervals of DO, D15, D30, D90 and D180. The Expanded Disability Status Scale (EDSS) and visual acuity tests were used to evaluate and differentiate the responses between the compared seropositive and seronegative cases. Results: A total of 17 outbreaks were evaluated: 7 optic neuritis (ON), 7 longitudinally extended transverse myelitis (LETM), 2 ON and LETM, 1 LETM and symptoms of TE. The patient mean age was 36.9 years; 12 patients were Affo-Brazilian and 5 Caucasian; and 14 female, 3 male. The mean time between the onset of the outbreak and plasmapheresis was 31 days. The mean EDSS score before the procedure was 7.35 and 5.75 after 180 days. The mean visual acuity on the Visual Outcome Scale was 5.6 pre-plas-mapheresis and 3.7 after 180 days. Complications were mostly related to catheter insertion (infection and hemothorax). There was no significant difference between seropositive and seronegative patients. Discussion and Conclusion: We believe that plasmapheresis is a safe and effective procedure in the treatment of exacerbations of NMO and NMO spectrum disorders, without difference in the response in relation to the AQP4. [ABSTRACT FROM AUTHOR]

Introduction: The relationship between aquaporin-4 antibody titers and cellular and inflammatory markers in cerebrospinal fluid (CSF) were analyzed in order to elucidate the immunopathogenetic role of aquaporin-4 (AQP4) antibodies in the CSF of neuromyelitis optica spectrum disorders (NMOSD). Materials and Methods: The study enrolled eleven consecutive NMOSD patients (10 female; 1 male) with a median age of 50 years (range 24-71 years) attending the Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo, Brazil. All had detectable AQP4 antibodies in serum and CSF samples. Astrocyte damage was evaluated measuring glial fibrillary acidic protein (GFAP) levels and cytokines were measured using a multiplexed fluorescent magnetic bead-based immunoassay of the CSF. Results: Serum AQP4 antibody titers were found at high-levels in all patients during attacks and remission. In contrast, AQP4 antibody titers in the CSF were remarkably higher only in samples collected during attacks. Consequently, the CSF:serum ratio found during remission (1:2,048±1:1,448) was higher than during NMO attacks (1:204+1:175), p=0.0030. The CSF AQP4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis (r=0.7679, p=0.0058), inflammatory cytokines including interleukin-6 (r=0.8091, p=0.0026) that can regulate antibody-producing plasmablasts, interleukin-1 beta (r=0.7517, p=0.0076) that can disrupt the blood-brain barrier, and GFAP levels (r = 0.9439, p<0.0001) in the CSF. Discussion and Conclusion: The amount of AQP4 antibodies present in the central nervous system may have therapeutic implications as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks. [ABSTRACT FROM AUTHOR]

Introduction: Longitudinally extensive spinal cord lesions on magnetic resonance imaging (MRI) are observed in a variety of diseases affecting the spinal cord. In some cases, the diagnosis can only be made by pathological analysis, despite the risks of surgical complications and sequelae. Longitudinally extensive transverse myelitis (LETM) stretching over three or more vertebral segments on MRI is commonly seen in neuromyelitis optica spectrum disorders (NMOSD). The presence of antibodies against aquaporin-4 (AQP4) is an important diagnostic biomarker of NMOSD. Materials and Methods: A review of the clinical, MRI and neuropathological clues in diagnosing neuromyelitis optica spectrum disorders (NMOSD) in two cases of AQP4 antibody-positive LETM, initially biopsied due to suspected spinal cord tumors. Results: We report two female patients (aged 14 and 47 years) with acute severe transverse myelopathy. Spinal cord MRI demonstrated T2-hyperintense longitudinally extensive lesions with swelling and contrast enhancement. Spinal cord biopsies excluded tumors but precluded definitive diagnoses. Both patients were later diagnosed with NMOSD based on their AQP4-seropositivity. Pathological review of both biopsies revealed demyelinated lesions with thickened vessel walls and tissue rarefaction. Immu-nohistochemical staining demonstrated findings compatible with acute NMOSD lesions. This included astrocyte loss in the lesion center and a lack of AQP4 staining, with relatively preserved myelinated fibers in one case. The other case exhibited reactive astrogliosis that partially lacked AQP4, which is consistent with chronic NMOSD lesions. Discussion and Conclusion: A pre-biopsy differential diagnosis of longitudinally extensive spinal cord tumors should include NMOSD. Specific biopsy features, such as cystic changes with vascular wall thickening and astrocyte injury, should raise suspicion for NMOSD. [ABSTRACT FROM AUTHOR]

Introduction: Investigation of the pathophysiology of multiple sclerosis (MS) points to a complex link between inflammation, synaptic dysfunction and neurodegeneration. The hippocampus plays a crucial role in declarative memory, one of the most common cognitive functions affected by the disease. The aim of this study was to investigate, in vivo, neuronal metabolites in the hippocampus of early MS patients using proton magnetic resonance spectroscopy (¹H-MRS) and their relation to verbal memory. Materials and Methods: Twenty-nine relapsing-remitting MS patients meeting the revised 2010 McDonald criteria (21 female; mean disease duration 2.5 years) and 26 healthy subjects were studied using ¹H-MRS with a 3.0 T Philips Achieva scanner. A single voxel with 10 x 15 x 40 mm was placed along the left hippocampus and the signal was collected using a PRESS sequence with different echo time (135 ms and 35 ms) and repetition time of 1500 ms. Data analysis was performed using the LC Model software and the concentration of metabolites weighted for content of tissue water and correction to the percentage of different tissue types inside the voxel. Intracranial and hippocampal volume measurements were obtained using FreeSurfer software. Subjects underwent a full neuropsychological battery from which a compound verbal memory score was extracted. Results: N-acetyl aspartate (NAA), creatine (Cr), choline compounds (Cho), myo-inositol (ml) and glutamine + glutamate (Glx) values were compared between groups and no statistically significant differences were found. Patient group revealed hippocampal atrophy of 8.7% (p=0.016) and a positive correlation of hippocampal volume and NAA (r=0.372; p=0.046). Multiple regression analysis indicated that after adjusting for age and education, neither hippocampal volume nor NAA was a significant predictor of memory score performance. Discussion and Conclusion: No significant metabolite alterations were detected in the hippocampus in the early stages of MS. Due to the presence of structural changes already observed, the levels of such metabolites, especially NAA, can represent adaptive mechanisms to overcome the burden of disease. [ABSTRACT FROM AUTHOR]

Introduction: Natalizumab is recommended for individuals who have not responded to first-line disease-modifying therapies for multiple sclerosis (MS) or who have very active disease. However, patients under natalizumab may develop progressive multifocal leukoencephalopathy (PML). Materials and Methods: A review was conducted of the use of natalizumab and the anti-JCV testing results among MS patients attending the outpatient clinic of the Hospital das Clínicas, University of São Paulo, Brazil. Results: Among the 1500 MS patients attending the outpatient clinic, 93 received natalizumab: 72 female, age range 21 - 56 years. Ninety patients had previously received immunomodulatory therapy and a half (n = 47) had received treatment with immunosuppressive drugs. Only two patients were treatment-naive. The average Expanded Disability Status Scale (EDSS) score was 3.5 (range: 1 - 6.5). After one year under treatment the EDSS was stable in 37% of patients and better (reduction of 1 point) in 63%. Less than 10% had a relapse in the first year of treatment. The presence of the anti-JCV antibody was positive in 18 patients at the first sample, of which, 12 (66.6%) had used immunosuppressant drugs. Seroconversion occurred in 4 negative patients approximately one year after the first test. One patient had progressive multifocal leukoencephalopathy (PML) but refused to be submitted to a JC virus test. Discussion and Conclusion: Patients who were treated with natalizumab showed a low number of MS relapses, whilst presenting stabilization or improvement in disability. However, anti-JCV+ patients are common in the Brazilian population and require careful evaluation through continuous clinical and imaging monitoring to avoid the development of PML. [ABSTRACT FROM AUTHOR]

Introduction: Natalizumab is a monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). It blocks lymphocytes from crossing the blood-brain barrier. While natalizumab is efficacious, long-term treatment is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). Many MS patients who have the 'triple risk' for PML - previous treatment with immunosuppressive drugs, positivity to JC virus, and natalizumab treatment - discontinue the drug infusions after some months, but alternatives are required to treat these patients. This study aimed to analyze factors leading to the interruption of natalizumab and alternative treatments initiated after its discontinuation. Materials and Methods: Ninety-three RRMS patients who had received natalizumab at least once were included. Information related to reasons for natalizumab discontinuation and subsequent initiations of alternative treatments were collected. Results: From the total, 25.8% (24/93) had discontinued natalizumab and the number of infusions ranged from 1 to 46. Nineteen patients ceased treatment due to the presence of the three risk factors for developing PML. Further reasons for discontinuation were: pregnancy, papilloma virus, ophthalmic herpes virus, and change of diagnosis. Treatment options after discontinuation included: rituximab, fingoli-mod, glatiramer acetate, azathioprin, or monthly pulses of methylprednisolone. Alternative treatments commenced 2-3 months after treatment with natalizumab was stopped. Discussion and Conclusion: The majority of MS patients discontinued natalizumab due to the presence of an increased risk of developing PML. Further studies are required to evaluate alternative treatment options and their efficacy and safety after natalizumab treatment in MS patients. [ABSTRACT FROM AUTHOR]

Introduction: Pain in inflammatory myelopathies is frequent but has not been clinically characterized. It is an appropriate model to assess pain mechanisms after spinal cord inflammatory lesions since there are no brain lesions that could bias pain assessment, cognition and mood assessment. It has been suggested that the prevalence and severity of pain syndromes among patients with neuromyelitis optica (NMO) and longitudinally extensive transverse myelitis (LETM) are greater in comparison to those with multiple sclerosis. It is not clear whether higher scores on the Expanded Disability Status Scale (EDSS) could influence pain and health-related quality of life scores. This study aimed to characterize disability, pain syndromes, and quality of life in this population. Materials and Methods: Patients with spinal cord-restricted demyelinating disease (last relapse at least 12 months prior to evaluation) and complaint of pain underwent a full physical examination and filled out a DN-4 questionnaire, Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI), McGill Pain Questionnaire (MPQ) and SF-12 Health Survey. Disability was assessed using the EDSS. Spasticity was measured using the Ashworth Scale. Patients were classified as at-level and below-level pain. Results: Twenty patients were included (15 female, 45.3±9.8 yr).Twelve (60%) were diagnosed as NMO, the remaining as LETM. At-level pain was present in 9 (45%) and below-level in 10 (50%). Thirteen (65%) patients had more than one pain syndrome. Results refer to the main pain syndrome. The median scores of the BPI (VAS) was 21.9±7.2; BPI interference 24.9±15.3; Mental Component Summary Scale of the SF12 49.5 ± 10.7; Physical Component Summary 33.0±10.3; NPSI 23.3±15.4; and MPQ 8.5±2.5. The median EDSS was 4.8±2.4 and Ashworth spasticity scale 1.35±1.1. The DN4 detected neuropathic pain (NeP) in 18 patients. Low back pain was a major pain complaint in 6 (30%) patients. Discussion and Conclusion: NeP is frequent in patients with inflammatory myelopathies. Low back pain was noted as the main pain syndrome in a significant proportion of patients. Mixed pain syndromes are the rule in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Self-report of balance problems is a recurrent issue in multiple sclerosis (MS) patients, even for those with minimal or no apparent clinical disability. Balance is a complex task that cannot be measured by either the Expanded Disability Status Scale (EDSS) or Romberg sign. For this reason, imbalance in patients with low disability is usually underestimated. The aim of this research was to investigate if measures of a sensory organization test could be used to detect subclinical balance disorders in MS. Materials and Methods: A total of 37 consecutive MS outpatients with low disability scores (EDSS 0-2.5) were evaluated. Patients were divided into two groups according to their self-report of balance issues: without balance problem (w/oBP, n=25) and with balance problem (w/BP, n=12). Balance was tested using the dynamic posturography equipment, Pro Balance Master (NeuroCom, Clakamas, Oregon, USA). The modified Sensory Organization Test (mSOT) was applied, measuring the relative contributions of visual, vestibular and somatosensory systems during standing. The subjects performed 3 x 20second trials under 4 different sensory conditions: eyes opened or eyes closed and support surface stable or unstable. The mSOT score for each condition ranges from 0 ( fall) to 100 (no sway). Statistical analysis was performed by the Mann-Whitney test and Student t-test. Results: EDSS scores were not significantly different between the groups. The mSOT test results revealed that the w/BP group had worse balance than the w/oBP under conditions 2 and 4 (p<0.01), both being eyes closed scenarios. Only one patient in the w/BP group had a positive Romberg result. Discussion and Conclusion: The results suggest that the mSOT is able to detect balance problems in MS patients with low disability scores, an issue not revealed by other tests. Balance was worse in the w/BP group than in the w/oBP group, particularly when vision was deprived and the support surface unstable. These findings indicate that impairment in sensorial integration areas is the primary cause of balance problems in MS. This study highlights the usefulness of objective measures of balance in the clinical setting for MS patients, regardless of disability status. [ABSTRACT FROM AUTHOR]

Introduction: Balance disorders are often the initial symptom in multiple sclerosis (MS) patients and should be considered an important aspect of mobility impairment and disability. Disability is usually evaluated by the Expanded Disability Status Scale (EDSS), however, many patients with low EDSS scores complain of balance issues, which are usually not recognized. The objective of this study was to evaluate balance control in MS patients with mild disability and self-report of balance problems. Materials and Methods: A total of 29 consecutive MS outpatients with relapsing-remitting disease and EDSS score between 0-2.5 were evaluated. Patients were divided into two groups according to balance complaint: without balance complaint (w/oBC, n=17) and with balance complaint (w/BC, n=12). Balance was tested using the dynamic posturography equipment, Pro Balance Master (NeurcCom, Clakamas, Oregon, USA). The Sensory Organization Test (SOT) was applied, providing information about the integration of the visual, proprioceptive and vestibular systems and leading to a value, called the Equilibrium Score (ES). Scores range from 0 ( fall) to 100 (complete stability). Statistical analysis was performed by the Mann-Whitney test and Student t-test. Results: No significant difference in EDSS scores were found between groups (p=0.4). The SOT test showed differences between groups (p<.05). The ES (+SD) values for the w/oBC and w/BC group were 75.41 (±10.47) and 63.17 (±9.91), respectively. Discussion and Conclusion: Balance control is directly related to mobility. Our results showed that EDSS is not able to detect mobility impairment in patients who have low disability, whereas the SOT was able to do so. Both EDSS and SOT tests evaluate sensory pathway information damage, but SOT elucidates how these sensorial systems impair balance control. This ability requires adequate cortical and cerebellar integration of sensorial information. The detection of low-level disabilities and subclinical disorders can be useful for rehabilitation purposes, as well as for evaluation of therapy outcomes. [ABSTRACT FROM AUTHOR]

Introduction : MRI has a central role in the investigation of demyelinating diseases. Conventional MRI is used for diagnostic and follow-up purposes and to characterize macroscopic lesions. However, it is limited in demonstrating strong clinical correlations or depicting underlying pathological aspects. Advanced MRI is gaining strength in the assessment of microstructural, metabolic and functional changes in brain disorders. The aim of this study was to discuss the role of those techniques. Materials and Methods : A PubMed literature search was conducted for the period between 2004 and 2014, using the keywords "multiple sclerosis" and "spectroscopy", "aspartate", "diffusion tensor imaging" (DTI) and magnetization transfer (MT) in order to identify publications discussing advanced MRI. A total of 28 papers studying MR spectroscopy, 54 DTI and 51 MT, were selected and classified by the field of research discussed by the techniques. Results : The differential diagnosis (DD) of demyelinating syndromes was assessed in 24.1% of the studies; MRI was the target for lesion evaluation in 33.1% and for normal appearing brain tissue (NABT) in 85%. Clinically isolated syndromes were assessed by 9.8% of the studies; 7.5% evaluated treatment effects and 30.1% gray matter pathology; 23.3% the clinical outcome; 29.3% showed functional/cognitive correlations; and 30.1% proposed pathological/histological discussions. Discussion and Conclusion : Advanced MRIs are not formally included in MS diagnostic criteria. They are, however, useful for the DD of MS phenotypes and allied disorders, to provide powerful information about the pathological background, to assess microstructural and occult damage in NABT and gray matter pathology, and are a promising tool for follow-up of the clinical outcome and functional status. [ABSTRACT FROM AUTHOR]

Introduction: The JC virus (JCV) is a double-stranded DNA polyomavirus associated with progressive multifocal leukoencephalopathy (PML). After systemic infection, the JCV can reach the central nervous system and infect oligodendrocytes but it does not cause any clinical manifestation if the immune surveillance is intact. JCV infection is thought to be one risk factor for developing PML during natalizumab treatment. The aim of the present study was to evaluate the prevalence of JCV in multiple sclerosis (MS) patients followed at the Hospital das Clinicas, University of São Paulo, Brazil. Materials and Methods: A total of 127 MS patients were tested for serum antibodies against JCV using the JCV test provided by Biogen Idee. Some patients were tested during natalizumab treatment, whilst others were tested before initiation of treatment. Results: Anti-JCV+ patients represented 54.3% (69/127) of the total. Ninety-eight patients were women, and the mean age was 34.9 years (range: 17-57 years). Among those patients receiving natalizumab (n=93), 18 were anti-JCV+ and 12 had prior use of immunosuppressive drugs. Four patients who were initially tested negative had serum conversion after one year of treatment. Discussion and Conclusion: The high seroprevalence of JCV in our patients confirms the importance of risk stratification and monitoring for MS patients selected to receive natalizumab treatment in Brazil. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is an important cause of disability in young adults. Primary progressive multiple sclerosis (PPMS) accounts for about 15% of patients with MS. This form of disease has different characteristics from the relapsing-remitting form (RRMS). PPMS has a progressive course from the onset of disease with a tendency to occur in patients at an older age, and affecting both genders equally. As yet, there is no effective treatment for this type of disease. The aim of this research was to study the epidemiological findings in a Brazilian population. Materials and Methods: A total of 34 MS patients were evaluated with a diagnosis of PPMS according to the revised 2010 McDonald criteria. ResuIts: Patient age ranged from 30-64 years with a median of 48.5 years. Average disease duration was 11 years. There was not a female majority as generally found in RRMS patients: males represented 66% of patients and females 44%. Caucasian patients corresponded to 70% of the total, black 10% and mulatto 20%. At the time of evaluation the median EDSS was 7, with a range of 6- 8.5. There was a predominance of cerebellar (11/34) and pyramidal signs (33/34). Discussion and Conclusion: It was concluded from the results that the community studied had similar epidemiological findings to those described in the scientific literature. These findings form part of an ongoing project. [ABSTRACT FROM AUTHOR]